Perioperative anaphylaxis is uncommon but devastating, occurring in roughly one in every 10,000 to 20,000 anesthetic procedures. What makes it especially treacherous is that patients under general anesthesia cannot communicate the early warning signs of a reaction. They cannot report itching, throat tightness, or dizziness. By the time the reaction announces itself, it is typically through falling blood pressure, a racing heart, or a sudden drop in oxygen saturation, all detected only if the anesthesiology team is watching closely. Neuromuscular blocking agents, the drugs that paralyze muscles to allow intubation and surgical access, are the most common triggers, and rocuronium bromide leads that list.

The four patients in the Japanese series ranged in age from 16 to 47, and two were women. Their reactions unfolded between 2 and 20 minutes after anesthesia induction, a window consistent with the rapid kinetics of drug-induced anaphylaxis. Every patient developed hypotension, and nearly all showed skin signs such as generalized erythema or wheals. One patient, however, experienced circulatory collapse before any meaningful rash appeared, with only mild erythema emerging afterward. That detail matters enormously, because skin findings are often treated as the hallmark of anaphylaxis, and their absence can delay diagnosis when seconds count.

Laboratory evidence bolstered the clinical picture in the cases where it was available. Serum tryptase, an enzyme released by mast cells during allergic activation, was elevated in both patients in whom it was measured. The researchers drew samples at 30 minutes, 2 hours, and 48 hours after symptom onset and observed increases of more than four times each patient’s baseline. The authors emphasize a point that is increasingly recognized in allergy practice: interpretation should rest not on absolute values but on the change from an individual’s baseline. Even tryptase levels that fall within the normal population range can be clinically significant if they rise sharply from a person’s own resting level, while an elevated baseline alone does not necessarily indicate anaphylaxis.

Confirming the culprit drug required careful skin testing, performed at previously recommended non-irritating concentrations to avoid false positives from the drugs’ inherent histamine-releasing properties. In one patient, a skin prick test at a maximum rocuronium concentration of 10 milligrams per milliliter, done three weeks after the event, produced a positive reaction. In the other three, prick tests were negative but intradermal tests at a maximum concentration of 0.1 milligrams per milliliter were positive. Saline and histamine served as negative and positive controls, with reactions read after 15 to 20 minutes and positivity defined by standardized wheal and erythema diameters. Tests for other suspected anesthetic agents were negative in all patients, and all four were diagnosed with rocuronium-induced anaphylactic shock. Encouragingly, subsequent surgeries were completed successfully without rocuronium.

The series also highlights the thorny problem of cross-reactivity among neuromuscular blocking agents. Previous studies have found that roughly 40 percent of patients allergic to rocuronium also test positive to vecuronium, and about 44 percent react to suxamethonium. This shared reactivity stems from the quaternary ammonium structure common to these drugs, and it means that simply swapping one paralytic for another is not automatically a safe strategy. Careful selection of alternative agents, guided by skin testing, is essential for any future anesthesia in these patients.

Timing of diagnostic testing presents its own dilemma. Current recommendations advise waiting at least 4 to 6 weeks after an anaphylactic event, because early testing can yield false negatives due to temporary depletion of mast cell mediators. Yet urgent clinical realities sometimes demand faster answers, particularly in patients with malignant disease or when surgical delay could worsen prognosis. One patient in this series was tested just three weeks after the reaction and still showed a positive prick test result, suggesting that early testing can be informative when the clinical context justifies it. The authors argue that testing schedules should be tailored to individual circumstances rather than applied rigidly.

Perhaps the most scientifically intriguing aspect of the series is what it reveals about mechanism. Two pathways have been proposed for rocuronium-induced anaphylaxis. The first is classic IgE-mediated allergy, in which sensitization to the quaternary ammonium structure shared by many neuromuscular blocking agents primes the immune system. Strikingly, that structure is ubiquitous in everyday life, present in cosmetics, detergents, and disinfectants. Environmental exposure may therefore sensitize people without their ever having received rocuronium, which could explain why several patients in this series and in prior reports suffered anaphylaxis despite no documented prior exposure to the drug.

The second pathway bypasses IgE entirely. Rocuronium has been identified as an agonist of MRGPRX2, a Mas-related G protein-coupled receptor on mast cells that can trigger degranulation directly. Reactions driven by this receptor may present predominantly with cardiovascular collapse and minimal or delayed skin manifestations. The fourth patient in the series, a 47-year-old man whose hypotension preceded any cutaneous symptoms and whose skin findings remained mild, fits that profile, although the authors caution that the mechanism could not be confirmed in his case. The implication for practice is sobering: anaphylaxis under anesthesia may announce itself with nothing more than a blood pressure crash, and clinicians must be prepared to intervene without the visual cue of a spreading rash.

In all four cases, prompt treatment made the difference. Management included immediate discontinuation of suspected agents, vasopressors, intravenous fluids, and epinephrine when necessary, and early recognition paired with rapid intervention stabilized every patient hemodynamically. The Tokyo team’s message to the wider medical community is twofold. First, perioperative anaphylaxis can occur even in patients with no documented prior exposure to rocuronium and may present without prominent skin findings, so vigilance during anesthesia is non-negotiable. Second, appropriately timed and appropriately dosed skin testing remains the cornerstone of diagnosis, enabling safe reoperation and informed avoidance of cross-reactive drugs. As surgical volumes grow worldwide, a complication that strikes only one in tens of thousands of procedures will never be rare in absolute terms, and studies like this one sharpen the tools clinicians need to catch it in time.

Subject of Research: Rocuronium bromide-induced perioperative anaphylaxis confirmed by skin testing in four patients

Article Title: Perioperative anaphylaxis caused by rocuronium bromide: a case series of four patients with skin test confirmation

Article References: Arai, S., Yoshihara, N., & Watanabe, R. (2026). Perioperative anaphylaxis caused by rocuronium bromide: a case series of four patients with skin test confirmation. Journal of Cutaneous Immunology and Allergy, 9, Article 16781. https://doi.org/10.3389/jcia.2026.16781

Image Credits: AI Generated

DOI: 10.3389/jcia.2026.16781

Keywords: perioperative anaphylaxis, rocuronium bromide, neuromuscular blocking agents, skin testing, tryptase, MRGPRX2, mast cells, IgE-mediated allergy, cross-reactivity, anesthesia, quaternary ammonium, case series